Project Summary The damage of optic nerve axons prevents the relay of the visual information from the eye to the brain, leading to the loss of vision. Therefore, our research has been focusing on developing methods to promote efficient optic nerve axon regeneration and to re-build functional visual pathways. Recent studies have led to the developments of several novel strategies that stimulate axon regeneration, however each of these methods only achieved regeneration in subsets of retinal ganglion cells (RGCs). Thus, to restore vision, new strategies are pressingly needed to promote regeneration of multiple types of RGCs. Inspired by the transcriptional reprogramming technology for obtaining iPS cells, we hypothesized that over-expressing certain transcription factors in adult RGCs could reprogram them into a young-RGC-like growth competent state. To this end, we have performed a screen for a list of transcription factors that are normally expressed during the differentiation stage of retinal progenitor cells, to examine which one(s), when overexpressed in adult RGCs, could enable significant axon regeneration using an intraorbital optic nerve injury model. Interestingly, we found that forced expression of the transcription factor Sox11, and to a less extent Sox4, resulted in marked optic nerve regeneration. Preliminary analysis revealed that the effects of Sox11 are likely different from those triggered by PTEN deletion (see Approach). Furthermore, while PTEN deletion promotes the regeneration selectively from alpha type of RGCs, Sox11 overexpression promotes the regeneration of melanopsin-expressing intrinsically photosensitive RGCs (ipRGCs) and other un-determined types of RGCs. These initial findings suggested a novel rationale for promoting optic nerve regeneration by reinstitute Sox11 expression. Here, we propose to explore the underlying mechanisms by which Sox11 stimulates RGC axon regeneration and its potential application, either by itself or in combination with others, in achieving functional recovery.